It has been known for some time that porphyrin related compounds accumulate at higher concentrations in tumor tissue as compared to normal tissue, and that irradiation of these compounds using light of the proper wavelength results in an energized form which, upon decay, results in cytotoxicity. These compounds have therefore been useful in PDT, a procedure for treating cancer that uses tumor-localizing photosensitizers.
The effectiveness of PDT is believed to be based on two toxic modes of action of photosensitizers. First, retained photosensitizers such as porphyrins cause localized necrosis of vascular tissue which in turn leads to cell death. The second mode of action involves exciting the photosensitizers by exposure to light. When porphyrins are exposed to light it is believed that singlet oxygen radicals are formed which directly damage cell walls leading to cell death. See, e.g., D. Kessel, Biochem. Soc. Trans. 5:139-40 (1977).
The use of porphyrin compounds in PDT has an unfortunate side effect--prolonged photosensitivity in the skin of treated patients persisting for several weeks. Efforts have been made in the art to reduce this side effect by minimizing the quantity of porphyrins required for PDT.
Hematoporphyrins, and hematoporphyrin derivatives (HPDs) are the primary porphyrin compounds used in PDT today. (See, e.g., "Porphyrin Photosensitization," Kessel, D. et al. eds. (1983 Plenum Press), R. L. Lipson et al., J. Natl. Cancer Inst. 26:1-8 (1961).) The maximum absorbance of hematoporphyrins and HPDs occurs at around 400 nm, but there is also absorbance around 630 nm, at a range where there is much scattering and absorbance by tissue. (See, e.g., A. M. Richter et al., J. Natl. Cancer Inst. 79:1327-32 (1987)).
Thus, one goal in the PDT field has been to find a suitable porphyrin derivative that has a maximum absorbance outside the range of tissue absorbance and scattering. One such class of porphyrins that is being studied is a set of modified porphyrins referred to as "green porphyrin" (also referred to as "Gp" herein) of which the hydro-monobenzoporphyrins ("BPDs") are a subclass. The disclosure of U.S. patent application Ser. No. 07/414,201, now U.S. Pat. No. 5,095,030, hereby incorporated by reference, discusses in detail the nature of Gp. The maximum absorbance of Gps are in the 670-780 nm range, where there is little tissue absorbance. The cytotoxicity of a BPD is discussed in A. M. Richter et al., J. Natl. Cancer Inst. 79:1327-32 (1987)
Another goal in PDT research has been to increase the specificity of the porphyrin compounds for the targeted tumor cells. Considerable advancements were made by conjugating hematoporphyrins to tumor-specific antibodies. In one case, for example, hematoporphyrin was covalently coupled to a monoclonal antibody directed to murine myosarcoma cells. D. Mew et al., J. Immunol. 130:1473-77 (1983).
A recent advancement in this direction is the discovery of the role of lipoproteins as carriers of porphyrins in serum. (See Reyftmann et al. Photochem. Photobiol. 40:721-29 (1984).) Lipoproteins have similarly been implicated in hematoporphyrin transport in Barel et al., Cancer Letters 32:145-50 (1986) and in BPD transport in Kessel et al., Photochem. Photobiol. 49:579-82 (1989).
Barel et al., supra, observed that formation of complexes of hematoporphyrin and low density lipoproteins (LDLs) led to more specific delivery to tumor tissue, although hematoporphyrin itself had a higher affinity for high density lipoproteins (HDLs). Similarly, Kessel et al., supra, observed that BPD compounds bound primarily to HDLs over other lipoprotein fractions.
The present invention is directed to the aforementioned problems and goals. The inventors herein have now discovered that precomplexation of certain BPDs with lipoprotein fractions results in increased specific delivery of photosensitizers to tumor cells. The amount of photosensitizer required for effective treatment is thereby reduced both by: (1) decreased absorbance of light at the drug absorption wavelength by the surrounding tissue; and (2) by increased specific delivery of the drug to tumor cells.